Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Biochem Biophys Res Commun. 2021 Jun 30;560:59-65. doi: 10.1016/j.bbrc.2021.04.130. Epub 2021 May 11.
The mitogen-activated protein kinase (MAPK) pathway plays an important role in the colorectal cancer (CRC) progression, being supposed to be activated by the gene mutations, such as BRAF or KRAS. Although the inhibitors of extracellular signal-regulated kinase (ERK) have demonstrated efficacy in the cells with the BRAF or KRAS mutations, a clinical response is not always associated with the molecular signature. The patient-derived organoids (PDO) have emerged as a powerful in vitro model system to study cancer, and it has been widely applied for the drug screening. The present study aims to analyze the association between the molecular characteristics which analyzed by next-generation sequencing (NGS) and sensitivity to the ERK inhibitor (i.e., SCH772984) in PDO derived from CRC specimens. A drug sensitivity test for the SCH772984 was conducted using 14 CRC cell lines, and the results demonstrated that the sensitivity was in agreement with the BRAF mutation, but was not completely consistent with the KRAS status. In the drug sensitivity test for PDO, 6 out of 7 cases with either BRAF or KRAS mutations showed sensitivity to the SCH772984, while 5 out of 6 cases of both BRAF and KRAS wild-types were resistant. The results of this study suggested that the molecular status of the clinical specimens are likely to represent the sensitivity in the PDOs but is not necessarily absolutely overlapping. PDO might be able to complement the limitations of the gene panel and have the potential to provide a novel precision medicine.
丝裂原活化蛋白激酶（MAPK）途径在结直肠癌（CRC）的进展中起着重要作用，被认为是通过基因突变（如 BRAF 或 KRAS）激活的。虽然细胞外信号调节激酶（ERK）的抑制剂已被证明在具有 BRAF 或 KRAS 突变的细胞中有效，但临床反应并不总是与分子特征相关。患者来源的类器官（PDO）已成为研究癌症的强大体外模型系统，并已广泛应用于药物筛选。本研究旨在分析下一代测序（NGS）分析的分子特征与结直肠标本来源的 PDO 对 ERK 抑制剂（即 SCH772984）敏感性之间的关联。使用 14 种 CRC 细胞系进行了 SCH772984 的药物敏感性测试，结果表明敏感性与 BRAF 突变一致，但与 KRAS 状态不完全一致。在 PDO 的药物敏感性测试中，7 例 BRAF 或 KRAS 突变中有 6 例对 SCH772984 敏感，而 6 例 BRAF 和 KRAS 野生型中有 5 例耐药。本研究结果表明，临床标本的分子状态可能代表 PDO 中的敏感性，但不一定完全重叠。PDO 可能能够弥补基因面板的局限性，并有可能提供新的精准医学。
